The objective of this study is to investigate the significance of viral gp120 sequences and cell specificity for AIDS pathogenesis using molecularly cloned SIVs. We have shown that cloned SIVmac239 and EVT3, differing only in their gp120 sequences, displayed distinct cell specificity in vitro and pathogenicity in vivo. In culture, EvT3 does not replicate in human T cell lines that are highly sensitive to SIVmac239 infection. In contrast, EvT3 replicated more efficiently in rhesus CD4+ T cell lines than SIVmac239. When experimentally infected into rhesus macaques, EvT3 induced severe and rapid CD4+ T cell depletion in peripheral blood and lymph nodes, accompanied by severe CD4+/CD8- thymocyte depletion in the thymus. In contrast, rhesus macaques infected with SIVmac239 did not show depletion of CD4+ T cells nor CD4+/CD8- thymocytes. We have found that virus load in peripheral blood, lymph nodes and the thymus from EvT3-infected macaques were approximately 10-fold higher than those from SIVmac239-infected macaques. We have been exploring to understand the molecular mechanisms by which the differences in cell specificity and gp120 sequences of EvT3 and SIVmac239 determine their pathogenic potentials in vivo. Recently, it has been shown that HIV-1 cell specificity is determined by their differences in chemokine receptor usages cytopathic or T cell-tropic HIV-1 utilized CXCR4, but CCR5 is preferentially utilized by non-cytopathic Mm-tropic HIV-1. Interestingly, we have found that EvT3 utilized CXCR4 as a co-receptor for virus entry similar to cytopathic HIV-1; however, SIVmac239 utilized CCR-5 as noncytopathic HIV-1 does. We hypothesize that CXCR4 usage of EvT3 plays an important role in the induction of CD4+ T cell depletion in vivo. Based on this hypothesis, we are currently investigating the significance of EvT3 CXCR4 usage as well as SIVmac239 CCR5 usage in determining the virus replication in CD4+ T cells and CD4+ thymocytes both in vitro and in vivo. The rhesus macaque AIDS model system using EvT3 and SIVmac239, differing in their gp120 sequences, cell specificity, chemokine receptor usage and pathogenic potential, would greatly facilitate the understanding of the basic mechanisms of AIDS pathogenesis in humans.